ABSTRACT
Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10â µg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1â µM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.
Subject(s)
Acridines , Enzyme Inhibitors , Oxidoreductases , Oxidoreductases/antagonists & inhibitors , Oxidoreductases/metabolism , Acridines/chemistry , Acridines/pharmacology , Acridines/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Molecular Dynamics Simulation , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Parasitic Sensitivity Tests , Dose-Response Relationship, Drug , Leishmania/drug effects , Leishmania/enzymology , Molecular Docking SimulationABSTRACT
Alzheimer's disease (AD) is a neurodegenerative process that compromises cognitive functions. The physiopathology of AD is multifactorial and is mainly supported by the cholinergic and amyloid hypotheses, which allows the identification the fundamental role of some markers, such as the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE-1), and the ß-amyloid peptide (Aß). In this work, we prepared a series of chalcones and 2'-aminochalcones, which were tested against AChE and BACE-1 enzymes and on the aggregation of Aß. All compounds inhibited AChE activity with different potencies. We have found that the majority of chalcones having the amino group are able to inhibit BACE-1, which was not observed for chalcones without this group. The most active compound is the one derived from 2,3-dichlorobenzaldeyde, having an IC50 value of 2.71 µM. A molecular docking study supported this result, showing a good interaction of the amino group with aspartic acid residues of the catalytic diade of BACE-1. Thioflavin-T fluorescence emission is reduced in 30 - 40%, when Aß42 is incubated in the presence of some chalcones under aggregation conditions. In vitro cytotoxicity and in silico prediction of pharmacokinetic properties were also conducted in this study.
Subject(s)
Chalcones/pharmacology , Cholinesterase Inhibitors/pharmacology , Protease Inhibitors/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/metabolism , Chalcones/pharmacokinetics , Chlorocebus aethiops , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacokinetics , Electrophorus , Humans , Mice , Molecular Docking Simulation , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Protein Binding , Protein Multimerization/drug effects , Vero CellsABSTRACT
Chagas disease is an endemic parasitic infection that occurs in 21 Latin American countries. New therapies for this disease are urgently needed, as the only two drugs available (nifurtimox and benznidazol) have high toxicity and variable efficacy in the disease's chronic phase. Recently, a new chemical entity (NCE) named Pyranaphthoquinone (IVS320) was synthesized from lawsone. We report herein, a detailed study of the physicochemical properties and in vitro trypanocidal activity of IVS320. A series of assays were performed for characterization, where thermal, diffractometric, and morphological analysis were performed. In addition, the solubility, permeability, and hygroscopicity of IVS320 were determined. The results show that its poor solubility and low permeability may be due to its high degree of crystallinity (99.19%), which might require the use of proper techniques to increase the IVS320's aqueous solubility and permeability. The trypanocidal activity study demonstrated that IVS320 is more potent than the reference drug benznidazole, with IC50/24 h of 1.49 ± 0.1 µM, which indicates that IVS320 has potential as a new drug candidate for the treatment of Chagas disease.
